Abstract
Approximately, 25–30% of early-stage breast tumors are classified at the molecular level as HER2-positive, which is an aggressive subtype of breast cancer. Amplification of the HER2 gene in these tumors results in a substantial increase in HER2 mRNA levels, and consequently, HER2 protein levels. HER2, a transmembrane receptor tyrosine kinase (RTK), is targeted therapeutically by a monoclonal antibody, trastuzumab (Tz), which has dramatically improved the prognosis of HER2-driven breast cancers. However, ~30% of patients develop resistance to trastuzumab and recur; and nearly all patients with advanced disease develop resistance over time and succumb to the disease. Mechanisms of trastuzumab resistance (TzR) are not well understood, although some studies suggest that growth factor signaling through other receptors may be responsible. However, these studies were based on cell culture models of the disease, and thus, it is not known which pathways are driving the resistance in vivo. Using an integrative transcriptomic approach of RNA isolated from trastuzumab-sensitive and trastuzumab-resistant HER2+ tumors, and isogenic cell culture models, we identified a small set of mRNAs and lincRNAs that are associated with trastuzumab-resistance (TzR). Functional analysis of a top candidate gene, S100P, demonstrated that inhibition of S100P results in reversing TzR. Mechanistically, S100P activates the RAS/MEK/MAPK pathway to compensate for HER2 inhibition by trastuzumab. Finally, we demonstrated that the upregulation of S100P appears to be driven by epigenomic changes at the enhancer level. Our current findings should pave the path toward new therapies for breast cancer patients.
Highlights
Breast cancer is a major health problem affecting millions of patients worldwide, and results in over 500,000 deaths annually
Using an integrative transcriptomic approach of RNA isolated from trastuzumab-sensitive and trastuzumab-resistant HER2+ tumors, and isogenic cell culture models, we identified a small set of mRNAs and lincRNAs that are associated with trastuzumab-resistance (TzR)
By applying generation RNA-sequencing to RNA isolated from human HER2+ tumors and cell culture models of the disease that are either trastuzumab-sensitive (TzS) or trastuzumab-resistant (TzR), we have identified a small set of mRNAs and lincRNAs that are strongly associated with TzR (Figure 1A)
Summary
Breast cancer is a major health problem affecting millions of patients worldwide, and results in over 500,000 deaths annually. HER2+ tumors are characterized at the molecular level by an amplification of a genomic region encompassing the HER2 gene ( known as HER2/neu and ERBB2), which is a member of the ERBB family of transmembrane receptor tyrosine kinases (RTKs) [1]. Trastuzumab (Herceptin®) is a monoclonal antibody that binds to the extracellular domain of the HER2 receptor, and is thought to inhibit its heterodimerization, and its signaling cascade [6]. A significant percentage of early-stage patients (~30%) relapse after this combination by unclear mechanisms [7]. It was hypothesized that resistance occurs due to shedding of the extracellular domain of HER2, and trastuzumab is no longer able to bind to HER2 [10], no experimental evidence has been presented to support this. It is clear that other mechanisms of resistance are at play in tumors in vivo
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